DESCRIPTION: (Applicant's Abstract) Substance abuse is the number one public health problem in the United States. Although the causes of addiction are complex and multifactorial, conditioning and learning factors may play a primary role in the development of addiction, and in particular in relapse to drug use. Despite the recognition that the occurrence of drug craving and relapse is in part driven by a learning process, and that drugs of abuse have clear effects on cellular plasticity, there has been very little attempt to integrate these two important notions, and to investigate the molecular mechanisms underlying conditioned responses to drug-related environmental cues. Data from both human and animal studies suggest that the prefrontal cortex is involved in the conditioned response to biological rewards and drug-related cues. An understanding of the complex pattern of cellular and genomic activity in prefrontal regions during conditioned craving could potentially be of great value to medications development. The process of addiction is likely to involve both temporary and permanent changes in gene expression and protein synthesis. However, progress has been limited by the extremely labor-intensive demands of investigating the role of individual genes or small groups of genes in complex cognitive or behavioral paradigms. The advent of DNA microarray technology is likely to change this limitation dramatically. This technology enables fast, parallel analysis of gene expression and the simultaneous monitoring of thousands of transcripts. We have recently developed a rat model of drug-associated classical conditioning. Thus, the question that forms the basis for this proposal is whether a distinct pattern of gene expression is observed in prefrontal cortex during exposure to drug-paired cues. We hypothesize that changes in the expression of specific genes are an essential component of the substrate for drug expectancy in animals (and perhaps drug craving in humans), and that the same sets of genes are involved in the conditioning response regardless of the addictive substance used. To test this hypothesis, we will apply DNA microarray analysis, employing several types of microarrays, to the drug conditioning paradigm. Our goal is to generate a "signature" of genes that are altered in the context of drug-related conditioning, with the ultimate aim of identifying molecular pathways important in this coqnitive state and behavior.